TY - JOUR
T1 - Aging can transform single-component protein condensates into multiphase architectures
AU - Garaizar, Adiran
AU - Espinosa, Jorge R.
AU - Joseph, Jerelle A.
AU - Krainer, Georg
AU - Shen, Yi
AU - Knowles, Tuomas P.J.
AU - Collepardo-Guevara, Rosana
N1 - Funding Information:
The research leading to these results received funding from the European Research Council (ERC) under the European Union's Horizon 2020 Framework Programme through Future and Emerging Technologies Grant NanoPhlow 766972 (to G.K. and T.P.J.K.), Marie Sklodowska-Curie Grant MicroSPARK 841466 (to G.K.), the European Union's Seventh Framework Programme FP7/2007-2013 through ERC Grant PhysProt 337969 (to T.P.J.K.), and ERC Grant InsideChromatin 803326 (to R.C.-G.).A.G. acknowledges funding from Engineering and Physical Sciences Research Council (EPSRC) Grant EP/N509620/ and the Winton Programme. We further thank the Oppenheimer Research Fellowship (J.R.E.), the Emmanuel College Roger Ekins Fellowship (J.R.E), the King's College Research Fellowship (J.A.J.), the Herchel Smith Funds (G.K.), theWolfson College Junior Research Fellowship (G.K.), the Newman Foundation (T.P.J.K.), the Biotechnology and Biological Sciences Research Council (T.P.J.K.),and theWinton Advanced Research Fellowship (R.C.-G.). We also acknowledge funding from Wellcome Trust Collaborative Award 203249/Z/16/Z (to T.P.J.K.). The simulations were performed using resources provided by the Cambridge Tier-2 system operated by the University of Cambridge Research Computing Service (https://www.hpc.cam.ac.uk/) funded by EPSRC Tier- 2 Capital Grant EP/P020259/1.
Funding Information:
We also acknowledge funding from Wellcome Trust Collaborative Award 203249/Z/16/Z (to T.P.J.K.). The simulations were performed using resources provided by the Cambridge Tier-2 system operated by the University of Cambridge Research Computing Service (https://www.hpc.cam.ac.uk/) funded by EPSRC Tier-2 Capital Grant EP/P020259/1.
Funding Information:
ACKNOWLEDGMENTS. The research leading to these results received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 Framework Programme through Future and Emerging Technologies Grant NanoPhlow 766972 (to G.K. and T.P.J.K.), Marie Skłodowska-Curie Grant MicroSPARK 841466 (to G.K.), the European Union’s Seventh Framework Programme FP7/2007-2013 through ERC Grant PhysProt 337969 (to T.P.J.K.), and ERC Grant InsideChromatin 803326 (to R.C.-G.). A.G. acknowledges funding from Engineering and Physical Sciences Research Council (EPSRC) Grant EP/N509620/ and the Winton Programme. We further thank the Oppenheimer Research Fellowship (J.R.E.), the Emmanuel College Roger Ekins Fellowship (J.R.E), the King’s College Research Fellowship (J.A.J.), the Herchel Smith Funds (G.K.), the Wolfson College Junior Research Fellowship (G.K.), the Newman Foundation (T.P.J.K.), the BiotechnologyandBiologicalSciencesResearchCouncil(T.P.J.K.),andtheWinton Advanced Research Fellowship (R.C.-G.).
Publisher Copyright:
Copyright © 2022 the Author(s).
PY - 2022/6/28
Y1 - 2022/6/28
N2 - Phase-separated biomolecular condensates that contain multiple coexisting phases are widespread in vitro and in cells. Multiphase condensates emerge readily within multicomponentmixtures of biomolecules (e.g., proteins and nucleic acids)when the different components present sufficient physicochemical diversity (e.g., in intermolecular forces, structure, and chemical composition) to sustain separate coexisting phases. Because such diversity is highly coupled to the solution conditions (e.g., temperature, pH, salt, composition), it can manifest itself immediately from the nucleation and growth stages of condensate formation, develop spontaneously due to external stimuli or emerge progressively as the condensates age. Here, we investigate thermodynamic factors that can explain the progressive intrinsic transformation of single-component condensates into multiphase architectures during the nonequilibrium process of aging.We develop a multiscale model that integrates atomistic simulations of proteins, sequence-dependent coarse-grained simulations of condensates, and a minimal model of dynamically aging condensates with nonconservative intermolecular forces. Our nonequilibrium simulations of condensate aging predict that single-component condensates that are initially homogeneous and liquid like can transform into gel-core/liquid-shell or liquid-core/gelshell multiphase condensates as they age due to gradual and irreversible enhancement of interprotein interactions. The type of multiphase architecture is determined by the aging mechanism, the molecular organization of the gel and liquid phases, and the chemical makeup of the protein. Notably, we predict that interprotein disorder to order transitions within the prion-like domains of intracellular proteins can lead to the required nonconservative enhancement of intermolecular interactions. Our study, therefore, predicts a potential mechanism by which the nonequilibrium process of aging results in single-component multiphase condensates.
AB - Phase-separated biomolecular condensates that contain multiple coexisting phases are widespread in vitro and in cells. Multiphase condensates emerge readily within multicomponentmixtures of biomolecules (e.g., proteins and nucleic acids)when the different components present sufficient physicochemical diversity (e.g., in intermolecular forces, structure, and chemical composition) to sustain separate coexisting phases. Because such diversity is highly coupled to the solution conditions (e.g., temperature, pH, salt, composition), it can manifest itself immediately from the nucleation and growth stages of condensate formation, develop spontaneously due to external stimuli or emerge progressively as the condensates age. Here, we investigate thermodynamic factors that can explain the progressive intrinsic transformation of single-component condensates into multiphase architectures during the nonequilibrium process of aging.We develop a multiscale model that integrates atomistic simulations of proteins, sequence-dependent coarse-grained simulations of condensates, and a minimal model of dynamically aging condensates with nonconservative intermolecular forces. Our nonequilibrium simulations of condensate aging predict that single-component condensates that are initially homogeneous and liquid like can transform into gel-core/liquid-shell or liquid-core/gelshell multiphase condensates as they age due to gradual and irreversible enhancement of interprotein interactions. The type of multiphase architecture is determined by the aging mechanism, the molecular organization of the gel and liquid phases, and the chemical makeup of the protein. Notably, we predict that interprotein disorder to order transitions within the prion-like domains of intracellular proteins can lead to the required nonconservative enhancement of intermolecular interactions. Our study, therefore, predicts a potential mechanism by which the nonequilibrium process of aging results in single-component multiphase condensates.
KW - biomolecular condensates
KW - hollow condensates
KW - liquid-liquid phase separation
KW - multiscale modeling multiphase condensates
UR - http://www.scopus.com/inward/record.url?scp=85132282378&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85132282378&partnerID=8YFLogxK
U2 - 10.1073/pnas.2119800119
DO - 10.1073/pnas.2119800119
M3 - Article
C2 - 35727989
AN - SCOPUS:85132282378
SN - 0027-8424
VL - 119
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 26
M1 - e2119800119
ER -